What every physician needs to know:

The upper limit of normal circulating eosinophils in the peripheral blood is 350 to 500/mm3. The severity of eosinophilia has been defined as follows:

Mild eosinophilia: 500 to 1,500 eosinophils/μl

Moderate eosinophilia: 1,500 to 5,000 eosinophils/μl

Severe eosinophilia: greater than 5,000 eosinophils/μl

The term “hypereosinophilia,” has been used to refer to an absolute eosinophil count of greater than 1,500/microl, thereby encompassing moderate and severe eosinophilia. In contrast, the term “hypereosinophilic syndrome” is usually reserved for hypereosinophilia (generally severe) occurring in the absence of an obvious underlying process.

Hypereosinophilic syndrome (HES) is a rare myeloproliferative disorder defined by sustained peripheral blood eosinophilia (greater than 1,500/mm3) and end-organ damage (heart, lung, skin) in the absence of evidence of any cause (such as parasitic disease, allergy, or neoplasia).

Chronic eosinophilic leukemia (CEL) is diagnosed when eosinophils are clonal or blasts are increased.

In the absence of a clonal marker, the clonality of HES is indeterminate, and it remains unknown how many of these patients have clonal disease.

Are you sure your patient has clonal hypereosinophilic syndrome? What should you expect to find?

As noted above, HES is associated with sustained moderate to severe eosinophilia. Clonal markers demonstrated by cytogenetics or fluorescence in situ hybridization (FISH) for the FIP1L1-PDGFRA gene fusion, establish a diagnosis of clonal HES. However, it is unknown how many of the patients who lack an easily identifiable clonal marker have clonal disease.

Of note, nearly half of the responding patients in the original study establishing the efficacy of imatinib in the treatment of HES, lacked a definable marker, suggesting that many of these patients have a clonal myeloproliferative disorder for which the molecular lesions remain undefined.

Beware of other conditions that can mimic clonal hypereosinophilic syndrome:

The differential diagnosis of eosinophilia distinguishes reactive (polyclonal) from primary (clonal) syndromes. The clonality of idiopathic hypereosinophilic syndrome in the absence of a clonal marker remains undefined.

Reactive (polyclonal):

Infection

Allergic/immune disorders

Drugs

Organ specific eosinophilic disorders

Paraneoplastic (solid or hematologic malignancy)

Aberrant T cell populations (lymphocyte variant HES)

Primary (clonal):

Acute myeloid leukemia (AML), myelodysplastic syndromes (MDS)

Myeloproliferative disorders (myeloproliferative variant HES)

Hypereosinophilic syndrome/chronic eosinophilic leukemia

Other MPDs with eosinophilia

Idiopathic hypereosinophilic syndrome

Which individuals are most at risk for developing clonal hypereosinophilic syndrome:

HES is a rare disease, occurring in less than 1/1,000,000 individuals. It occurs predominantly in individuals between the ages of 20 and 50 years, and is more common in men than in women.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

The laboratory evaluation of eosinophilia is outlined in the “Eosinophilia” chapter. Briefly, laboratory development is directed at ruling out secondary eosinophilia:

What imaging studies (if any) will be helpful in making or excluding the diagnosis of clonal hypereosinophilic syndrome?

N/A

If you decide the patient has clonal hypereosinophilic syndrome, what therapies should you initiate immediately?

Identification of the FIP1L1-PDGFRA fusion or other clonal cytogenetic abnormality is diagnostic of clonal HES, and treatment with imatinib should be begun promptly. Required imatinib doses may be quite low, compared to those required to treat chronic myelogenous leukemia (CML). Usual therapeutic dosing is 100 to 400 mg/day. A short course of steroids is recommended when initiating imatinib, as it may reduce toxicity of the initial treatment.

In patients in whom the diagnosis is uncertain but in whom an alternative reason for secondary eosinophilia is not identified, it is reasonable to initiate a trial of imatinib. The drug is very well-tolerated, and many patients without the diagnostic translocation still respond to imatinib. Indeed, nearly half of the responding patients in the original reported trial did not have evidence of the FIP1L1-PDGFRA fusion gene. In myeloproliferative HES, an elevated tryptase may be a marker of aggressive disease, but is also predictive of imatinib response.

More definitive therapies?

In patients responding to imatinib, treatment with tyrosine kinase inhibitors should be continued indefinitely. This will usually lead to complete and durable molecular responses. Cessation of imatinib leads to relapse, although most patients can be salvaged with reinstitution of therapy. Imatinib resistance is very rare, but can arise from mutation in the tyrosine kinase domain in a manner that parallels that seen with CML. Treatment with other tyrosine kinase inhibitors (TKIs) may overcome resistance, although there is one mutation (FIP1L1-PDGFRα D842V) that is highly resistant to all TKIs.

It is not known why imatinib resistance is so rare in CEL/HES, but is thought to reflect the fact that cells with the FIP1L1-PDGFRA mutation are 100-fold more sensitive to imatinib than BCR-ABL.

In patients who do not respond to TKIs, especially in the absence of a clonal marker confirming the diagnosis of clonal HES, alternative therapies include hydroxyurea, alpha interferon, and anti-IL5 (interleukin-5) antibody.

What other therapies are helpful for reducing complications?

As previously noted, steroids for 1-2 weeks at the initiation of imatinib may prevent toxicity resulting from the rapid lysis of eosinophils.

What should you tell the patient and the family about prognosis?

Patients with clonal HES who respond to TKIs have an excellent prognosis. They need to continue to take imatinib indefinitely, as cessation of therapy is associated with relapse. However, continued imatinib is associated with durable and complete responses with rare toxicity.

Patients with non-clonal hypereosinophilia have variable prognosis related to the disease underlying their eosinophilia. This is discussed in the general chapter on eosinophilia.

"What" if scenarios.

Patient does not have a clonal marker for HES

If the patient does not have evidence for a secondary form of eosinophilia or a lymphoma-related HES, and has symptoms related to end-organ damage, an empiric trial of imatinib seems reasonable.

Patients with significant cardiac infiltration with eosinophils may develop acute cardiac problems upon initiation of imatinib. It is recommended that patients receive a short course of steroids upon initiation of imatinib therapy, although there are limited definitive data demonstrating the efficacy of this approach.

Patient wants to discontinue imatinib

Discontinuation of imatinib therapy is not recommended in patients with a good clinical and/or molecular response to imatinib, since the disease does not appear to be cured by the therapy. However, relapsed patients usually can be salvaged with restarting TKI therapy.

Pathophysiology

Many cases of clonal HES harbor the FIP1L1-PDGFRA fusion gene. FIP1L1-PDGFRA is a fusion protein generated by an interstitial deletion on chromosome 4. HES associated with PDGFRA fusion proteins are in the spectrum of classic myeloproliferative diseases, where translocation leads to constitutive tyrosine kinase activity and hyperproliferation. Point mutations of PDGFRA have also been identified in HES and likely also result in constitutive kinase activity.

Interestingly, mice expressing FIP1L1-PDGFRA in a bone marrow transplant model develop a myeloproliferative neoplasm without eosinophilia. Why this fusion protein in humans predominantly manifests in the eosinophilic lineage is unknown. A few studies have suggested that cooperation of FIP1L1-PDGFRA with interleukin 5 (IL-5) may promote eosinophil proliferation. PDGFRA mutations account for 10 to 20% of HES. Other mutations associated with myeloproliferative clonal HES include abnormalities in PDGFRB or FGFR1.

Eosinophilia may also be seen in association with myeloid leukemia, most notably M4 leukemia. The cause of the eosinophilia is unknown. Eosinophilia in association with T-cell lymphoma may be associated with hypersecretion of IL5.

The pathophysiology of idiopathic HES is unknown.

What other clinical manifestations may help me to diagnose clonal hypereosinophilic syndrome?

N/A

What other additional laboratory studies may be ordered?

As previously noted, a tryptase level predicts for a higher likelihood of end-organ damage from HES, but also predicts for TKI-responsive HES.

What’s the evidence?

Cools, J, DeAngelo, DJ, Gotlib, J. “A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome”. N Engl J Med.. vol. 348. 2003. pp. 1201[Original description of the characteristic fusion gene in HES and its response to imatinib. Of note, half of the responding patients did not have a FIP1L1-PDGFRA fusion.]